Document bB7Oq45m52LLBBov4zz85DgOO

Center for Regulatory Effectiveness Tel: (202)W216a1s5whD-wi2nu3wpgS8.otT3ounhnitte,eCCD7FiRr.0aCcE0xl.e.:c,o(2N2m00.0W23).6939-6969 November 29, 2000 Via FedX Dr. Mary S. Wolfe Executive Secretary RoC Subcommittee o f the NTP Board o f Scientific Counselors NIEHS Building 101, Room A322 111 TW Alexander Drive Research Triangle Park, NC 27709 (919) 541-3971 Dear Dr. Wolfe: Attached are written comments for distribution to the individual members o f the RoC Subcommittee o f the NTP Board o f Scientific Counselors for consideration prior to their public review o f substances nominated for listing in the 10thReport on Carcinogens on December 13-15 in Washington, DC. Public comment on the proposed listings was solicited in the Federal Register notice o f October 17, 2000, 65 Fed.Reg. 61352. Our comments focus solely on the proposed listing for non-asbestiform talc (i.e., talc not containing asbestiform fibers). I am submitting these comments on behalf o f the Center for Regulatory Effectiveness ("CRE"). CRE is not affiliated with any particular industry, company, or other entity. It was established in 1996 at the urging o f Members o f Congress to assist in analysis o f federal regulatory and quasi-regulatory issues likely to be o finterest to Congress, particularly proposed rules that would require Congressional review under the Congressional Review Act. Since then, it has expanded its mission into related areas. O fparticular relevance to this proceeding is its goal o f reviewing federal programs that involve dissemination o f information to the public to ensure that such information is o f the highest quality, and utility to the public, in accordance with the goals o f Congress in enacting the data quality provisions o f the Paperwork Reduction Act o f 1995. CRE has no members, but it receives, from time to time, financial support, services in kind, and work product from trade Protected Document - Subject to Protective Order 1 of 12 IMERYS 100151 PltfJMERYS_00tMEftYS100151 Center for Regulatory Effectiveness -2- associations and private firms. Consequently, at any one time, CRE benefits from the input or advice o f literally hundreds o f small and large firms. I have also registered to make an oral presentation in connection with the RoC Subcommittee's review o f non-asbestiform talc at the December 13-15 meeting. Sincerely, Attachment William G. Kelly; Jr. Western States Representative Center for Regulatory Effectiveness 184 Mt. Owen Dr. Driggs, ID 83422 Phone: (208) 354-3050 Fax: same E-mail: .......... Protected Document - Subject to Protective Order 2 of 12 IMERYS 100152 PltfJMERYS 00IMERYS100152 Center for Regulatory Effectiveness November 29, 2000 COMMENTS BY CRE ON THE LISTING PROPOSED FORTHTAELRCEPNOORTTCOONNCTAARINCIINNGOGAESNBSE,STTEIFNOTRHMEDFIITBIEORNS IN Presented to the RoC Subcommittee o f the NTP Board o f Scientific Counselors for Consideration at its Peer Review Meeting December 13-15, 2000, in Washington, DC Introduction The Center for Regulatory Effectiveness ("CRE") has been closely monitoring and commenting on the RoC program since the advent o freviews for the 9thRoC. (See the CRE website at www.thecre.com.) CRE's interest in this program stems from the feet that Congress intended the Reports to be informative to members o fthe general public, rather than a document for the scientific community. Therefore, CRE has been particularly interested in how the RoC and its review committees have handled nominations for exposures o f interest to large segments o fthe U.S. public, as opposed to exposures which are primarily o f occupational interest. CRE's interest is based onthe realistic appreciation that the Reports are documents which can substantially impact consumer choices and behavior - in effect, operating as a kind o f indirect regulation o f the listed exposures in contrast to direct regulation. Such indirect regulation has the potential to conflict with safety or risk assessments made by federal agencies, such as FDA or EPA, to whom Congress has delegated responsibility for direct regulation. More broadly, CRE has an established interest in seeing that the Congressional mandates concerning the quality o f information disseminated to the public by government agencies, contained in the Paperwork Reduction Act o f 1995, are fully implemented. As expressed in the stated Congressional goals o f that Act, agencies should ensure that the information they disseminate is accurate, up-to-date, objective, clear, and useful to the public. CRE also has an established interest in ensuring that federal agencies adhere faithfully to their own rules in developing and disseminating information to the public. After making numerous recommendations for improvement in the RoC program during preparation o f the 9thRoC (some o f which have been adopted, and others not), CRE has continued - 1- Protected Document - Subject to Protective Order 3 of 12 IMIEMRYESR10Y01S53100153 Center for Regulatory Effectiveness to monitor the program during preparation o f the 10thRoC. In doing so, it has found that some o f the same substantial deficiencies it commented on during the 9thRoC reviews have persisted into the current 10thRoC reviews. In reviewing the various 10thRoC Draft Background Documents and public comments, CRE has been struck particularly by glaring deficiencies in assessment o fthe listing proposalfor non-asbestiform talc. Since exposure to non-asbestiform talc, particularlyin its cosmetic form, is o fwide consumer interest, CRE has chosen to review and comment directly on this proposed listing. In doing so, CRE has concluded that the listing proposals by RG1 and RG2 reflected in the Draft Background Document (`DBD") contain a number o f fatal flaws which make it impossible for the RoC Subcommittee members, and subsequent reviewers, to concur with theproposed "reasonably anticipated" human carcinogen listing. These fatal flaws, discussed in more detail below, include: 1. In its assessment o f the evidence from studies in humans, the DBD fails repeatedly and at critical points to differentiate between evidence concerning asbestiform and non-asbestiform talc, and effectively concedes that it is not possible to determine whether the human studies relied on involved exposures to non-asbestiform talc. In place o f scientific evidence regarding whether the human exposures were to nonasbestiform talc, the DBD substitutes assumption and policy for scientific evidence, contrary to Congressional intent and the weight o f the evidence. 2. The DBD recommendations for listing o f non-asbestiform talc as "reasonably anticipated" to cause cancer in humans are based on a combination o f (a) conclusions regarding the relevance o fthe epidemiologic evidence, and (b) conclusions regarding evidence from animal studies. The epidemiologic evidence is admitted to be inadequate, and there is no finding o f "sufficient" animal evidence consistent with the listing criteria and established interpretations o f the criteria. With regard to (b), the DBD omits discussion o fthe conclusion reached by FDA scientists that the evidence from the single NTP animal study relied on is not relevant to human exposures. 3. The DBD treats "reasonably anticipated" as equivalent to "possibly", "suggested", or "may", contrary to the plain meaning o f "reasonably anticipated" and judicial precedent. Detailed Discussion 1. The DBD presentation o f evidence from studies in humans demonstrates, on its face, that the epidemiologic evidence is inadequate to support a listing for non-asbestiform talc, because it cannot differentiate non-asbestiform talc from talc containing asbestiform fibers in its assessment. The listing nominations, as presented in the April 5,2000, Federal Register notice (65 Fed. Reg. 17899), presented separate nominations for "Talc (Non-Asbestiform)" and "Talc (Containing Asbestiform Fibers)". In describing the separate exposures, only non-asbestiform talc was described as being used in cosmetic products. 2- - Protected Document - Subject to Protective Order 4 of 12 IMERYS 100154 Pltf_IMERYS_jMERYSl00154 Center for Regulatory Effectiveness The RG1 and RG2 listing recommendations contained in the DBD contain separate recommendations for asbestiform and non-asbestiform talc. While the two groups differed on the appropriate listing for asbestiform talc, they concurred on recommending to list talc not containing asbestiform fibers as "reasonably anticipated to be a human carcinogen", based on epidemiologic studies o f ovarian cancer in woman who used "cosmetic talc" and a single animal study. The summaries or the RG1 and RG2 evaluations o f the evidence from studies in humans, however, immediately evidence a fatal flaw o f failing to differentiate asbestiform from nonasbestiform talc. In summarizing this evidence supposedly supporting a listing o f non-asbestiform talc as "reasonably anticipated" to cause human cancer, both review groups refer to the studied exposure simply as "cosmetic talc", then "talc", and then comment that the substance was "(presumably cosmetic grade, but information on fibrous content is lackingV' (At iii and v, emphasis added.) In other words, it is not known whether the exposure in those epidemiologic studies was in fact cosmetic talc not containing asbestiform fibers. This failure to differentiate the evidence is all the more surprising because, immediately following the above statements regarding the epidemiologic evidence, both groups differentiate between talc with asbestiform fibers and non-asbestiform talc in summarizing the evidence from studies in animals. This deficiency, and confusion, is carried forward in the Introduction to the DBD (p. 1) in the statement that "[a] number o f human and experimental animal carcinogenicity studies o f talc have been published since the IARC listing [decision in 1987 to classify non-asbestiform talc as having inadequate evidence o f carcinogenicity]. . . that suggest an association between exposure to non-asbestiform talc (including cosmetic talc! and cancer risk in humans." (Emphasis added.) The DBD then proceeds to explain that cosmetic talc may, in the 1960s and 1970s, have contained significant quantities o f asbestiform fibers, but that currently such tab may be free o f such contamination. In the section on "Asbestiform talc", the DBD states: Although talcs can be virtually free o f fibrous materials, they also have been reported to contain asbestos fibers in quantities sometimes constituting almost halfthe total product weight (Dement and Zumwalde 1979). Surveys published in the late 1960s and 1970s trem olite, reported that talcum powders and anthophyllite fibers that cmonatyaibneedomf aeasbsuerstaibfolermamnoautnutrseo(fRcohhryl seottialel, 1976). However, the purity o f cosmetic talc appears to have improved as a result o f voluntary guidelines proposed bv the cosmetic industry in 1976 (see Section 2). At 5. In the portion o f Section 2 ("Human Exposure") apparently referred to in the above quotation, the DBD, after noting that the FDA has considered talc as GRAS (Generally Recognized as Safe) for use in cosmetics, states: -3- Protected Document - Subject to Protective Order 5 of 12 IMERYS 100155 Pltf_IMERYS_00dMyS100155 Center for Regulatory Effectiveness Under the voluntary guidelines initiated in 1976, the CFTA [sic1] stated that all cosmetic talc should contain at least 90% platy talc that is free o f detectable amounts o f fibrous minerals, including asbestos. . . . At 15. As is apparent from the two separate nominations and the discussion in the DBD, the distinction between talc containing and not containing asbestiform fibers is critical. "Talc" without contamination with asbestiform fibers, particularly that used for cosmetic purposes, has unique physical and chemical characteristics that distinguish it from asbestiform fibers. Basically, talc is a platy material, a hydrous magnesium silicate, with unique softness and lubricating qualities due to the ability o f the platy structures to slide easily over each other. Asbestiform fibers, on the other hand, lack these qualities and are fibrous, rather than platy, materials with different chemical/mineralogical compositions. As stated in the DBD: `"Asbestiform habit' refers to the unusual crystallization habit o f a mineral in which the crystals are thin, hairlike fibers.. .. Asbestiform describes a special type o f fibrosity.. . . In particular, the term `asbestiform' has been used in a variety o f ways in the past, sometimes applying only to asbestos or to fibers that look like asbestos." At 4-5. The DBD discussion o f possible mechanisms o f carcinogenicity for asbestiform and nonasbestiform talc (pp. 65-72) illustrates the lack o f relevant evidence on mechanism for nonasbestiform talc, while emphasizing that the probable mechanism for asbestiform talc carcinogenicity is dependent on the fibrous structure o f the asbestiform content. In contrast to the ambiguous and conflicting summarization o f evidence concerning nonasbestiform talc, the DBD is very clear about the asbestiform nature o f the evidence supporting the recommendations for listing asbestiform talc. The RG1 and RG2 summaries state that "[s]tudies o f facilities where the talc was known to have contained" asbestiform fibers give the strongest evidence o frisk. (At iii and v, emphasis added). The RG1 summary adds the statement that "[tjhese studies are supported by the prior listing o f asbestos as a known human carcinogen in the Report on Carcinogens (1980)." (At iii.) The above discussion is but a prelude to a key portion o f the DBD demonstrating the lack o f evidence for listing non-asbestiform talc. In section 3.3, pp. 28-29, which concludes the section on evidence from studies in humans, titled "Talc containing asbestiform fibers and talc not containing asbestiform fibers", the DBD admits this lack o f human evidence, but nevertheless proceeds to surmount this insurmountable obstacle to listing by employing both an assumption about the current composition o f (apparently all) talc and recommending a listing for an exposure that has not even been nominated - namely "undifferentiated talc" - when the formal listing nominations require differentiation. In effect, the DBD concludes that all forms o ftalc should be regarded as asbestiform, 1 Presumably this should be CTFA, the Cosmetic, Toiletry & Fragrance Association. -4- Protected Document - Subject to Protective Order 6 of 12 IMEJRMYSE10y01S56100156 Center for Regulatory Effectiveness unless they really are non-asbestiform! After concluding that evidence from studies o f asbestiform talc exposures in the talc mining and milling industries indicates that talc containing asbestiform fibers is carcinogenic, the DBD goes on to state: Neither occupational studies conducted outside o fthe talc and pottery industries nor the extensive literature concerning cancer and perineally applied talcum powder provide any characterization o ftalc mineralogy or morphology that could be used to determine the effects o f different kinds o f talc. However, because o f the widespread contamination o f "talc"and commercial talc products with asbestiform minerals, it must be assumed that "talc" without further specification o f mineralogy or morphology may contain asbestos fibers. The weight o f the evidence thus indicates that it would be prudent to regard such undifferentiated talc materials as carcinogenic. At 28, emphasis added. As discussed above, the DBD recognizes that there are commercial talcs, particularly ones used in cosmetic products, that may be virtually free o f asbestiform fibers, and that whatever information there was on "widespread contamination" with asbestiform fibers comes from the 1960s and 1970s and prior to the time the industry took steps to ensure that consumer talc would not contain asbestiform fibers. No scientific support is cited for such an "assumption" o f current widespread contamination; and assumptions are not "evidence". Perhaps the most noteworthy aspect o f this quoted DBD statement is the frank admission that the epidemiologic studies on cosmetic talc are inadequate to serve as evidence pertinent to assessing the effects o f non-asbestiform talc. The use o f assumptions and policy (i.e, "prudence") is also in conflict with recorded Congressional intent concerning preparation o f the Reports on Carcinogens. The statements o f legislative intent make it clear that the listings in the Reports are to be based on "data" and "reasonable grounds", and there is no reference to employment o f assumptions or policy.2 This human evidence section o f the DBD then proceeds to discuss the occupational studies in humans in which there was exposure to non-asbestiform talc (also confusingly referred to as "talc that did not contain asbestos"). The DBD concludes that those studies are not adequate to support any conclusions about the carcinogenicity o f non-asbestiform talc. However, the DBD then surprisingly in effect restates its unsupported position that "undifferentiated talc" should be regarded as carcinogenic: "In contrast [to the occupational studies involving non-asbestiform talc], the evidence from studies o f ovarian cancer suggests that talcum powder is a carcinogen." (At 29, emphasis added.) There is no nomination pending for "talcum powder", only distinct nominations for asbestiform talc and talc not containing asbestiform fibers. 2 SeeH .R R ep.N o 1192,95thCong., 2d Sess. at 28 (May 15,1978); statement o fMr. Rogers in Cong. Rec.- House, Oct. 10,1978, at 34938; and the Joint House-Senate Comparative Summary and Explanation in Cong. Rec. - House, Oct. 14, 1978, at 38657. -5- Protected Document - Subject to Protective Order 7 of 12 IMERYS 100157 PltfJMERYS_00MESyS100157 Center for Regulatory Effectiveness Consequently, based on the analysis presented in the DBD, the conclusion is inescapable that there is not adequate scientific evidence from studies in humans to support listing talc which does not contain asbestiform fibers, whether used in cosmetics or otherwise, as "reasonably anticipated" to cause cancer in humans. 2. Since the evidence from studies in humans is admitted to be inadequate, the only support for a listing o f non-asbestiform talc is a single controversial animal study, and the discussion and conclusions in the DBD are not adequate to show compliance with the listing criteria. In addition, the DBD omits discussion o f the conclusions reach bv FDA that the single animal study is not relevant for determining risk from realistic human exposures. The criteria for listing in the "reasonably anticipated" category are set out at page i o f the DBD. Since, as established above, the DBD concedes that the evidence from studies in humans cannot be assessed for relevance to listing non-asbestiform talc, under the criteria the proposed listing must be supported by "sufficient" evidence from studies in experimental animals which shows, as relevant here, tumors in "multiple species, or at multiple tissue sites". The DBD relies on only a single animal study, and neither the RG1 nor RG2 summary in the DBD contains a finding that there was "sufficient" evidence from that study in experimental animals, as required by the criteria; instead, both summaries simply state that there is "evidence" o f carcinogenicity from a "study" in experimental animals. (At iii and v.)3 The Introduction to the DBD (p. v) contains the same ambiguous statement. Likewise, the extended discussion o f the study in Section 4 o f the DBD does not contain a summary evaluation o f the study as providing "sufficient" evidence to support a "reasonably anticipated" listing; instead, as in the RG1 and RG2 summaries and the Introduction, it simply states that the study provides "evidence" for carcinogenicity. (At 46.) A similarly ambiguous statement is made in Section 6, in the portion concerning possible mechanisms o f action. The DBD states: The NTP (1993) concluded that there was some evidence o f carcinogenic activity o f non-asbestiform, cosmetic-grade talc in male F344/N rats, based on an increased incidence o f pheochromocytoma o f the adrenal gland. There was clear evidence o f carcinogenic activity in female F344/N rats, based on increased incidences o f alveolar or bronchiolar adenoma and carcinoma o f the lung and pheochromocytoma o f the a(Gdroeondaml galann1d9. 9H5.oOwebveerrd,otrhseterrel1e9v9a5n.ceZoazfethnesskeireetsaull.ts1t9o9h5u)m. a.n.s.has been questioned Lung tumors were not induced in male rats or in male or female mice in the NTP (1993) study. . . . 3 While the single "study" referred to in these statements is not specified, it is obviously the 1993 NTP inhalation study in rats and mice, referred to in the DBD as "NTP 1993". 6- - Protected Document - Subject to Protective Order 8 of 12 IMERYS 100158 Pltf IMERYS 00WERVS100158 Center for Regulatory Effectiveness (At 67, emphasis added.) In brief, there is only one study showing increased tumorigenicity in a single species o f animal (rat), with "some evidence" for adrenal tumors, and "clear evidence" for lung/bronchial tumors, although it is acknowledged that some experts regard the evidence as not relevant to humans. Since the listing criteria for the "reasonably anticipated" category require "sufficient" evidence in either multiple species or at multiple tissue sites, the DBD does not contain a finding that the criteria are satisfied. To examine this issue o f whether the criteria could be considered satisfied by these sorts o f conclusions regarding evidence o f tumorigenicity in a single study o f a single species at two tissue sites, one must determine whether the evidence is "sufficient" for both sites, as that term is used in the listing criteria. Although the listing criteria do not define the term "sufficient", the term has acquired recognized meaning through established practice. The term "sufficient" is used to describe the necessary degree o f evidence in both the IARC criteria and the RoC criteria. The 7thRoC (1994), in discussing the relationship between the RoC criteria and the IARC criteria, commented that "[although the IARC and the Annual Report's!4] schemes do not exactly correspond to one another, the Annual Report's scheme and associated degrees o f evidence are based on IARC's classification scheme and degrees o f evidence." At 6. The revisions to the RoC criteria in 1996 retained the term "sufficient" without any indication o f change in meaning. The Preambles to the IARC Monographs contain a discussion o f how animal studies should be evaluated, which indicates that "sufficiency" requires that a study be "adequate", and that determinations o f adequacy must take into consideration, among other issues, "how clearly the agent was defined", "whether the dose was adequately monitored, particularly in inhalation experiments", and "whether the doses and duration o f treatment were appropriate". (Section 9(a).) The term "sufficient" is also defined by IARC in a manner which casts light on the "multiple tissue sites" portion o f the revised RoC criteria. The IARC definition states: "Exceptionally, a single study in one species might be considered to provide sufficient evidence o f carcinogenicity when malignant neoplasms occur to an unusual degree with regard to . . . site . . . ." Apparently more relevant, however, is the IARC definition o f the term "limited evidence" in connection with animal experiments, since "limited" is considered to be not "sufficient". IARC considers animal evidence to be "limited" rather than "sufficient" if "there are unresolved questions regarding the adequacy o f the design, conduct, or interpretation o f the study." As indicated by the DBD in the quotation above from page 67, there are clearly significant "unresolved questions regarding the adequacy o f the design, conduct, or interpretation" o f the 1993 NTP animal study for determining its relevancy to humans. In fact, the DBD eventually concludes that the evidence should not be considered relevant to humans under any exposure conditions that could be reasonably anticipated: The current data indicate that inhaled non-asbestiform talc is unlikely to pose a cancer risk to humans under exposure conditions that do not impair clearance mechanisms or cause chronic lung toxicity. At 71-72. 4 A 1993 legislative amendment converted the RoC from an "Annual Report" to a biennial report. -7- Protected Document - Subject to Protective Order 9 of 12 IMERYS 100159 Pltf IMERYS 00(MERYS100159 Center for Regulatory Effectiveness An RoC conclusion that the NTP animal study should be considered relevant to human risk under reasonably anticipated exposure conditions would also apparently conflict with conclusions reached by FDA personnel who have legislative responsibility for direct regulation o f unsafe ingredients in cosmetics under the Food, Drug and Cosmetic Act. Although it is not referred to or discussed in the the DBD, in 1994, as a result o f concerns regarding the 1993 NTP animal study, the FDA and the International Society for Regulatory Toxicology and Pharmacology co-sponsored a workshop to discuss the study and see whether they could arrive at any consensus views on how it should be interpreted. Twenty FDA scientists participated, along with numerous scientists from academia, industry, cancer research institutions, NIEHS, NCI, and other organizations.5 At the beginning o f the workshop, Dr. John Bailey, Director o f FDA's Office o f Cosmetics and Colors, presented the "Introduction: Overview - Scope o f the Workshop", in which he stated: . . . I think it is reasonable to expect by the end o f the workshop to have a discussion or even to reach a consensus o f the many scientific and medical experts that are participating in and attending this meeting about the relevance o f the recent reports to the safety o f talc to human health risks. Id. at 216. Indeed, the Executive Summary prepared by the Rapporteur, Dr. Jelleff Carr, explains the consensus that was reached: A final panel included most speakers and other experts and was able to reach an unanimous assessment o f the workshop. In regard to the NTP talc bioassay in rodents, it found that because o f the extreme doses and the unrealistic particle sizes o f the talc employed, because o f the negative results in mice and male rats, because o fthe lack o ftumor excesses at the low doses, and because o fthe clear biological and cytological markers o f excessive toxicity in female rats, the positive talc bioassay results in female F344/N rats are the likely experimental artifact and nonspecific generic response o f dust overload o f the lungs and not a reflection o f direct activity o f talc. Given the gross differences o f rodent and human lungs, the lung clearance capabilities o f humans, and the possible conditions o f customary human exposures, the NTP bioassay results in F344/N female rats cannot be considered as relevant predictors o f human risk. Id. at 215. These published conclusions and related papers should have been referenced and discussed in the DBD, and should certainly be considered by the RoC Subcommittee in evaluating whether the NTP bioassay constitutes "sufficient evidence" for purpose o fsupporting a listing o fnonasbestiform talc as "reasonably anticipated" to cause cancer in humans. 3. The DBD treats "reasonably anticipated" as equivalent to "suggested", or "may", contrary to the plain meaning o f that phrase. Congressional intent, and judicial precedent. 5 Perspectives" in RTehge.wToorxk. sPhhoaprpmr.o2ce1e(d2i)n:2g1s 1a-n6d0p(a1p9e9rs5w). ere published as "Talc: Consumer U ses and Health 8- - Protected Document - Subject to Protective Order 10 of 12 IMERYS 100160 Pltf_IMERYS_00dMEfiYS100160 Center for Regulatory Effectiveness "Anticipated" is a synonym for "expected" or "predicted"; it indicates a reasonable degree of certainty, and is not equivalent to "may[be]". Nevertheless, key statements in the DBD assessments for non-asbestiform talc use terms such as "suggested" and "may". The Introduction o f the DBD states that human and animal studies o f"talc" "suggest an association" between non-asbestiform talc and cancer. (At 1, emphasis added.) The section on epidemiologic studies concludes that "[tjaken together, current case-control studies suggest an association o f ovarian cancer with genital exposure to talc." (At 25, emphasis added.)6 The same section concludes with the statement that "the evidence from studies o f ovarian cancer suggests that talcum powder is a carcinogen." (At 29, emphasis added.)7 "Talc may contain asbestiform fibers." (At 4, emphasis added.) "[I]t must be assumed that `talc' without further specification o f mineralogy or morphology may contain asbestos fibers." (At 28, emphasis added.) During Congressional consideration o f the RoC legislation, the original bill called for fisting as either a "known" or "suspected" human carcinogen. However, in the final legislation, Congress decided to change "suspected" to "reasonably anticipated".8 C"aonutniccipilJavut.eddEic"RiarAlepq(ru1ei9cre8eds7e)"n,ctNocnRlevDainrClcyinadsgiss"atiienlevgdiudieasnshceaesrtbohitferataedrryvmeEr"PsaeAnt'esifcffiepacialttuser.de"ItfonrotNmaak"teupironastlsoiRbalecesc"oo,uuinrncdteicsnauDtimnegfeertnohusaest health risks that might ("may") be connected with fluoride when the agency set drinking water standards for fluoride. The U.S. Court o f Appeals for the District o f Columbia Circuit stated: NRDC cites studies purporting to find a link between fluoride and a host o f health problems. Under the SDWA, however, the RMCL is to be set with reference to known or anticipated adverse health effects, not merely possible effects. 42 U.S.C. 3OOg-1(b)(1)(B). EPA reviewed and responded to the studies in fair detail and gave reasoned explanations for finding that they did not convincingly establish a cognizable connection between fluoride in drinking water and the various health risks posited. 812 F.2d 721, 725 (D.C. Cir. 1987) (emphasis added). 6 Note that the DBD does not even claim that these studies establish that "causal interpretation is credible", as required by the RoC criteria, or that they even establish an "association"; they only "suggest" one; and an "association" can be far short o f a credible causal relationship, as required by the "reasonably anticipated" criteria. Apparently an association is only "suggested" because only one-halfo fthe 16 studies contained statistically significant positive results. At 28. In addition, the DBD states that "positive risk estimates remain after adjustment for confounders; however, ovarian cancer is far from being well-understood, and one cannot adjust for a confounder that is not known and the effect o f which is uncertain. 7 Note again that "talcum powder" is not a substance that has been nominated for listing; only talc containing asbestiform fibers and talc not containing asbestiform fibers have been separately nominated. 8 Joint House-Senate Comparative Summary and Explanation in Cong. Rec. - House, Oct. 14, 1978, at 38657. -9- Protected Document - Subject to Protective Order 11 of 12 IMERYS 100161 Pltf IMERYS 00IMERYS100161 Center for Regulatory Effectiveness Summary 1. On its face, the DBD concludes that the evidence from studies in humans is inadequate to support any listing o f talc not containing asbestiform fibers in the RoC because it cannot be determined whether the exposures in those studies were to asbestiform or non-asbestiform talc (or possibly other substances also). 2. The DBD does not contain a finding that the animal evidence is sufficient within the meaning o f the fisting criteria to support a fisting o f talc not containing asbestiform fibers, and a number o f DBD statements indicate that RGland RG2 concluded that the animal evidence was not "sufficient" and not relevant to any reasonably anticipated human exposures. 3. FDA scientists reviewed the relevant animal evidence and concluded that it was not relevant to any expected human exposures. 4. Key conclusions in the DBD are based on a "possible" connection between exposure to nonasbestiform talc and human cancer and therefore cannot support a fisting as "reasonably anticipated" to cause cancer in humans. 5. In view ofthe above, the DBD cannot support a fisting o f non-asbestiform talc as "reasonably anticipated" to cause cancer in humans. Recommended RoC Subcommittee Actions The lack o f scientific support for fisting talc not containing asbestiform fibers is clear. The deficiencies in the DBD are fundamental and cannot be cured by clarifications or qualifications. Consequently - 1. The Subcommittee should vote unanimously against any listing o f talc not containing asbestiform fibers, possibly with a recommendation for deferral o f consideration o f listing until it appears that sufficient relevant scientific evidence has accumulated.9 2. In view o f the fatal deficiencies in the DBD, if a majority o f the Subcommittee were to vote in favor o f listing, it should provide a reasoned explanation for how its action comports with the RoC fisting criteria. Even if a minority supports listing o f talc not containing asbestiform fibers, those individual members voting in support o f fisting should explain how their position comports with the fisting criteria. Thank you for your thoughtful consideration o f these comments. 9 Deferral would be consistent with the recommendations made by the RoC Subcommittee (as well as RG1 and RG2) regarding boot and shoe manufacture and repair during consideration of listings for the 9thRoC. The Subcommittee recommended deferral based on doubts as to whether there was adequate evidence relevant to current exposures in the United States. - 10- Protected Document - Subject to Protective Order 12 of 12 IMERYS 100162 Pltf IMERYS 00fflftVS1Q0162